Ethamoxytriphetol

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Ethamoxytriphetol
Ethamoxytriphetol.svg
Clinical data
Other namesMER-25; NSC-19857
Routes of
administration
By mouth
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H33NO3
Molar mass419.55582 g/mol g·mol−1
3D model (JSmol)

Ethamoxytriphetol (developmental code name MER-25) is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed.[1] MER-25 was first reported in 1958, and was the first antiestrogen to be discovered.[2][3][4] It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested".[1][2] However, some estrogenic effects in the uterus have been observed,[2] so it is not a pure antiestrogen (that is, a silent antagonist of the estrogen receptor (ER)) but is, instead, technically a selective estrogen receptor modulator (SERM).[5] For all intents and purposes, it is a nearly pure antiestrogen, however.[6]

MER-25 produces antifertility effects in animals, and garnered interest as a potential hormonal contraceptive.[3][4] However, clinical development was discontinued due to its low potency and the incidence of unacceptable central nervous system side effects,[3][4][7] including hallucinations and psychotic episodes, with higher doses.[8][9] Undesirable gastrointestinal side effects were also described.[7] Prior to being discontinued, the drug was also administered by Roy Hertz to three patients with metastatic breast cancer and was found to provide relief from bone pain, presumably due to dissolution of bone metastases.[10][8] This was the first such study of its kind of antiestrogen therapy for the treatment of breast cancer, and it led to the development of the highly successful tamoxifen for this indication a decade later.[8] The drug was also evaluated for the purpose of ovulation induction and as a treatment of chronic mastitis and endometrial cancer before clinical development was stopped.[9]

MER-25, a simple triphenylethanol derivative,[6][4] is closely related structurally to the triphenylethylene (TPE) group of SERMs, which includes clomifene and tamoxifen.[2] The drug, a derivative of the cholesterol-lowering agent triparanol (MER-29) (which itself was derived from the estrogen chlorotrianisene (also known as TACE)),[9][11] was originally being studied in animals at Merrell Dow as a treatment for coronary artery disease.[4] Its antiestrogen properties were discovered serendipitously when a young research endocrinologist at the company named Leonard Lerner, who was employed to study nonsteroidal estrogen pharmacology, noted the structural similarity of MER-25 to estrogenic TPE derivatives and decided to test it for estrogenicity, only to find that it blocked the effects of estrogen instead.[4] Lerner subsequently went on to be involved in the discovery of clomifene, the first considerably antiestrogenic TPE derivative to be characterized.[4] The structure of clomifene is similar to that of its predecessor, MER-25.[4][7] Clomifene is about 10-fold more potent than MER-25.[7]

See also[edit]

References[edit]

  1. ^ a b Janos Fischer; C. Robin Ganellin; David P. Rotella (15 October 2012). Analogue-based Drug Discovery III. John Wiley & Sons. pp. 5–. ISBN 978-3-527-65110-8.
  2. ^ a b c d Philipp Y. Maximov; Russell E. McDaniel; V. Craig Jordan (23 July 2013). Tamoxifen: Pioneering Medicine in Breast Cancer. Springer Science & Business Media. pp. 7–. ISBN 978-3-0348-0664-0.
  3. ^ a b c Virgil Craig Jordan (1986). Estrogen/antiestrogen Action and Breast Cancer Therapy. Univ of Wisconsin Press. pp. 28, 154. ISBN 978-0-299-10480-1.
  4. ^ a b c d e f g h V Craig Jordan (27 May 2013). Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health: Progress and Promise. World Scientific. pp. 7, 112. ISBN 978-1-84816-959-3.
  5. ^ Jacques Balthazart; Gregory Ball (15 November 2012). Brain Aromatase, Estrogens, and Behavior. OUP USA. pp. 161–. ISBN 978-0-19-984119-6.
  6. ^ a b JORDAN V. CRAIG; B.J.A. Furr (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 4, 161. ISBN 978-1-59259-152-7.
  7. ^ a b c d Harper, Michael J. K. (1968). "Pharmacological Control of Reproduction in Women": 47–136. doi:10.1007/978-3-0348-7065-8_2. Cite journal requires |journal= (help)
  8. ^ a b c William B. Pratt (1994). The Anticancer Drugs. Oxford University Press. pp. 21–. ISBN 978-0-19-506739-2.
  9. ^ a b c Andrea Manni (15 January 1999). Endocrinology of Breast Cancer. Springer Science & Business Media. pp. 286–287. ISBN 978-1-59259-699-7.
  10. ^ Fritz F. Parl (1 January 2000). Estrogens, Estrogen Receptor, and Breast Cancer. IOS Press. pp. 13–. ISBN 978-0-9673355-4-4.
  11. ^ Enrique Ravina (11 January 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 178–. ISBN 978-3-527-32669-3.